Basal cell carcinoma (BCC) is a common epithelial tumor. Its incidence increases with increasing age. Current treatments for BCC's include the surgical excision of the tumor together with a margin of normal tissue and, when surgery is not feasible or desirable, destruction of the tumor cells by ionizing radiation or other means. Although scarring and disfigurement are potential side effects, surgical excisions that do not leave neoplastic cells behind can provide cure. Radiation therapy acts by causing irreparably high quantity of DNA-damage which, in turn, triggers apoptotic death of the tumor cells. This mode of action of radiation-therapy, i.e. apoptosis secondary to DNA-damage, is similar to those of many chemotherapeutic agents that are currently used in the treatment of cancers. However, both radiation therapy and the cytotoxic cancer chemotherapeutics are capable of causing DNA-damage in the normal cells of patients in addition to the tumor cells. As a result, their effectivity and usefulness in cancer therapy are seriously limited. A further dilemma with the use of radiation and genotoxic cancer chemotherapeutics is the disturbing fact that, even when cure of the primary tumor is achieved, patients have markedly increased risk of developing new cancers because of the DNA-damage and the resulting mutations they have undergone during the treatment of primary tumor. Induction of apoptosis selectively in tumor cells by non-genotoxic means would therefore be most desirable in the field of cancer therapy.
BCC's frequently show inactivating mutations of the gene patched which encodes a transmembrane protein acting as a receptor for the hedgehog proteins identified first by their effect on the patterning of tissues during development. When not liganded by hedgehog, the patched protein acts to inhibit intracellular signal transduction by another transmembrane protein, smoothened. Binding of hedgehog to the patched causes relieving of this inhibition. Intracellular signal transduction by the relieved smoothened then initiates a series of cellular events resulting ultimately in alterations of the expressions of the hedgehog target genes and of cellular behaviour. General features of this hedgehog/smoothened pathway of signal transduction, first identified in Drosophila, are conserved in diverse living organisms from Drosophila to Human. However, the pathway gets more complex in more advanced organisms (e.g. presence in human of more than one genes that display significant similarity to the single patched gene of Drosophila). Inactivating mutations of the patched have been found to cause constitutive (ligand-free) signalling through the hedgehog/smoothened pathway. The hedgehog/smoothened pathway overactivity, resulting from mutations of the patched and/or further downstream pathway elements, is found in all BCC's. The nevoid basal cell carcinoma syndrome (NBCCS) results from patched haploinsufficiency. Patients with the NBCCS, because of an already mutant patched in all cells, develop multiple BCC's as they grow older. Hedgehog/smoothened signalling is known to be employed for normal functions in several normal tissues and for the maintenance of normal epithelial stem cells (Zhang Y et al (2001) Nature 410:599-604).
Cyclopamine, a steroid alkaloid, has the chemical formula shown below.

It is found naturally in the lily Veratrum californicum and can be obtained by purification from this and other sources. Inhibition of the hedgehog/smoothened pathway by cyclopamine has been found in chicken embryos and in cultured cells of mice. Cyclopamine has been found to inhibit the differentiation of neuronal precursor cells in developing brain (Incardona J P et al (1998) Development 125:3553-3562; Cooper M K et al (1998) Science 280:1603-1607). Studies with other differentiating cell types have also reported an inhibitory action of cyclopamine on cellular differentiation. Differentiation of bone marrow cells to erythroid cells (Detmer K. et al (2000) Dev. Biol. 222:242) and the differentiation of urogenital sinus to prostate (Berman D M et al (2000) J. Urol. 163:204) have been found to be inhibited by cyclopamine. Inhibition of hedgehog/smoothened signalling by cyclopamine has been reported to exert no significant effect on the viability of cells (Taipale J. et al (2000) Nature 406; 1005-1009).